Glucopyranosyloxypyrazole derivatives, medicinal compositions containing the same and intermediates in the production thereof

ABSTRACT

The present invention relates to glucopyranosyloxypyrazole derivatives represented by the general formula: 
                         
wherein R 1  represents a hydrogen atom or a lower alkyl group; one of Q 1  and T 1  represents a group represented by the general formula:
 
                         
while the other represents a lower alkyl group or a halo(lower alkyl) group; and R 2  represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a halo(lower alkyl) group or a halogen atom, or pharmaceutically acceptable salts thereof, which have an inhibitory activity in human SGLT2 and are useful as agents for the prevention or treatment of diabetes, diabetic complications or obesity, and to pharmaceutical compositions comprising the same and intermediates thereof.

This is a divisional of U.S. Ser. No. 10/759,138 filed Jan. 20, 2004,which is a continuation of U.S. Ser. No. 10/069,589 filed Feb. 27, 2002,now abandoned, which was an application under 35 U.S.C. 371 ofPCT/JP00/05678 filed Aug. 24, 2000, claiming the benefit of JP246800/1999 filed Aug. 31, 1999, the disclosures of which are herebyincorporated by reference.

TECHNICAL FIELD

The present invention relates to glucopyranosyloxypyrazole derivativesor pharmaceutically acceptable salts thereof, which are useful asmedicaments, pharmaceutical compositions comprising the same andintermediates thereof.

BACKGROUND ART

Diabetes is one of lifestyle-related diseases with the background ofchange of eating habit and lack of exercise. Hence, diet and exercisetherapies are performed in patients with diabetes. Furthermore, when itssufficient control and continuous performance are difficult, drugtreatment is simultaneously performed. Now, biguanides, sulfonylureasand insulin sensitivity enhancers have been employed as antidiabeticagents. However, biguanides and sulfonylureas show occasionally adverseeffects such as lactic acidosis and hypoglysemia, respectively. In acase of using insulin sensitivity enhancers, adverse effects such asedema occasionally are observed, and it is also concerned for advancingobesity. Therefore, in order to solve these problems, it has beendesired to develop antidiabetic agents having a new mechanism.

In recent years, development of new type antidiabetic agents has beenprogressing, which promote urinary glucose excretion and lower bloodglucose level by preventing excess glucose reabsorption at the kidney(J. Clin. Invest., Vol. 79, pp. 1510–1515 (1987)). In addition, it isreported that SGLT2 (Na⁺/glucose cotransporter 2) is present in the S1segment of the kidney's proximal tubule and participates mainly inreabsorption of glucose filtrated through glomerular (J. Clin. Invest.,Vol. 93, pp. 397–404 (1994)). Accordingly, inhibiting a human SGLT2activity prevents reabsorption of excess glucose at the kidney,subsequently promotes excreting excess glucose though the urine, andnormalizes blood glucose level. Therefore, fast development ofantidiabetic agents, which have a potent inhibitory activity in humanSGLT2 and have a new mechanism, has been desired. Also, since suchagents promote the excretion of excess glucose though the urine andconsequently the glucose accumulation in the body is decreased, they arealso expected to have a preventing or alleviating effect on obesity.

As compounds having pyrazole moiety, it is described that WAY-123783increased an amount of excreted glucose in normal mice. However, itseffects in human are not described at all (J. Med. Chem., Vol. 39, pp.3920–3928 (1996)).

DISCLOSURE OF THE INVENTION

The present invention relates to a glucopyranosyloxypyrazole derivativerepresented by the general formula:

wherein R¹ represents a hydrogen atom or a lower alkyl group; one of Q¹and T¹ represents a group represented by the formula:

while the other represents a lower alkyl group or a halo(lower alkyl)group; and R² represents a hydrogen atom, a lower alkyl group, a loweralkoxy group, a lower alkylthio group, a halo(lower alkyl) group or ahalogen atom, or a pharmaceutically acceptable salt thereof.

Also, the present invention relates to a pharmaceutical composition,which comprise as an active ingredient a glucopyranosyloxypyrazolederivative represented by the general formula:

wherein R¹ represents a hydrogen atom or a lower alkyl group; one of Q¹and T¹ represents a group represented by the formula:

while the other represents a lower alkyl group or a halo(lower alkyl)group; and R² represents a hydrogen atom, a lower alkyl group, a loweralkoxy group, a lower alkylthio group, a halo(lower alkyl) group or ahalogen atom, or a pharmaceutically acceptable salt thereof.

Furthermore, The present invention relates to aglucopyranosyloxypyrazole derivative represented by the general formula:

wherein R¹ represents a hydrogen atom or a lower alkyl group; one of Q²and T² represents a 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy group,while the other represents a lower alkyl group or a halo(lower alkyl)group; and R² represents a hydrogen atom, a lower alkyl group, a loweralkoxy group, a lower alkylthio group, a halo(lower alkyl) group or ahalogen atom, or a salt thereof, and to a benzylpyrazole derivativerepresented by the general formula:

wherein R^(2′) represents a lower alkyl group, a lower alkoxy group, alower alkylthio group, a halo(lower alkyl) group or a halogen atom; andR^(3′) represents a lower alkyl group, or a salt thereof.

BEST MODE FOR CARRYING OUT THE INVENTION

The present inventors have studied earnestly to find compounds having aninhibitory activity in human SGLT2. As a result, it was found thatglucopyranosyloxypyrazole derivatives represented by the above generalformula (I) exhibit an excellent inhibitory activity in human SGLT2 asmentioned below, thereby forming the basis of the present invention.

This is, the present invention relates to a glucopyranosyloxypyrazolederivative represented by the general formula:

wherein R¹ represents a hydrogen atom or a lower alkyl group; one of Q¹and T¹ represents a group represented by the formula:

while the other represents a lower alkyl group or a halo(lower alkyl)group; and R² represents a hydrogen atom, a lower alkyl group, a loweralkoxy group, a lower alkylthio group, a halo(lower alkyl) group or ahalogen atom, or a pharmaceutically acceptable salt thereof, apharmaceutical composition comprising the same and an intermediatethereof.

In the compounds represented by the above general formula (I), the term“lower alkyl group” means a straight-chained or branched alkyl grouphaving 1 to 6 carbon atoms such as a methyl group, an ethyl group, apropyl group, an isopropyl group, a butyl group, an isobutyl group, asec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group,a neopentyl group, a tert-pentyl group, a hexyl group or the like; theterm “lower alkoxy group” means a straight-chained or branched alkoxygroup having 1 to 6 carbon atoms such as a methoxy group, an ethoxygroup, a propoxy group, an isopropoxy group, a butoxy group, anisobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxygroup, an isopentyloxy group, a neopentyloxy group, a tert-pentyloxygroup, a hexyloxy group or the like; and the term “lower alkylthiogroup” means a straight-chained or branched alkylthio group having 1 to6 carbon atoms such as a methylthio group, an ethylthio group, apropylthio group, an isopropylthio group, a butylthio group, anisobutylthio group, a sec-butylthio group, a tert-butylthio group, apentylthio group, an isopentylthio group, a neopentylthio group, atert-pentylthio group, a hexylthio group or the like. The term “halogenatom” means a fluorine atom, a chlorine atom, a bromine atom or aniodine atom; and the term “halo(lower alkyl) group” means the abovelower alkyl group substituted by different or same 1 to 3 halogen atomsas defined above.

In the substituent R¹, a hydrogen atom or a straight-chained or branchedalkyl group having 1 to 3 carbon atoms are preferable; and a hydrogenatom, an ethyl group, a propyl group or an isopropyl group are morepreferable. In the substituent R², a straight-chained or branched alkylgroup having 1 to 4 carbon atoms, a straight-chained or branched alkoxygroup having 1 to 3 carbon atoms, or a straight-chained or branchedalkylthio group having 1 to 3 carbon atoms are preferable; and an ethylgroup, an ethoxy group, an isopropoxy group or a methylthio group aremore preferable. In the substituents Q¹ and T¹, it is preferable thateither of them is a straight-chained or branched alkyl group having 1 to3 carbon atoms, and it is more preferable that either of them is amethyl group.

For example, the compounds represented by the above general formula (I)of the present invention can be prepared according to the followingprocedure:

wherein X and Y represent a leaving group such as a halogen atom, amesyloxy group or a tosyloxy group; R³ represents a lower alkyl group ora halo(lower alkyl) group; R⁴ represents a methyl group or an ethylgroup; R⁵ represents a lower alkyl group; one of Q² and T² represents a2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy group, while the otherrepresents a lower alkyl group or a halo(lower alkyl) group; and R¹, R²,Q¹ and T¹ have the same meanings as defined above.Process 1

A compound represented by the above general formula (IV) can be preparedby condensing a benzyl derivative represented by the above generalformula (II) with a ketoacetate represented by the above general formula(III) in the presence of a base such as sodium hydride or potassiumtert-butoxide in an inert solvent. As the inert solvent used in thereaction, 1,2-dimethoxyethane, tetrahydrofuran, N,N-dimethylformamide, amixed solvent thereof and the like can be illustrated. The reactiontemperature is usually from room temperature to reflux temperature, andthe reaction time is usually from 1 hour to 1 day, varying based on aused starting material, solvent and reaction temperature.

Process 2

A pyrazolone derivative represented by the above general formula (V) canbe prepared by condensing a compound represented by the above generalformula (IV) with hydrazine or hydrazine monohydrate in an inertsolvent. As the inert solvent used in the reaction, toluene,tetrahydrofuran, chloroform, a mixed solvent thereof and the like can beillustrated. The reaction temperature is usually from room temperatureto reflux temperature, and the reaction time is usually from 1 hour to 1day, varying based on a used starting material, solvent and reactiontemperature. The obtained pyrazolone derivative represented by the abovegeneral formula (V) can be also used in process 3 after converting intoa salt thereof in usual way.

Process 3

-   (1) In case of pyrazolone derivatives represented by the above    general formula (V) wherein R³ is a lower alkyl group, a    corresponding compound represented by the above general    formula (VII) can be prepared by subjecting a corresponding    pyrazolone derivative represented by the above general formula (V)    to glycosidation using acetobromo-α-D-glucose in the presence of a    base such as silver carbonate in an inert solvent, and subjecting    the resulting compound to N-alkylation using an alkylating agent    represented by the above general formula (VI) in the presence of a    base such as pottasium carbonate in an inert solvent as occasion    demands. As the solvent used in the glycosidation reaction,    tetrohydrofuran and the like can be illustrated. The reaction    temperature is usually from room temperature to reflux temperature,    and the reaction time is usually from 1 hour to 1 day, varying based    on a used starting material, solvent and reaction temperature. As    the solvent used in the N-alkylation reaction, acetonitrile,    N,N-dimethylformamide, tetrohydrofuran, a mixed solvent thereof and    the like can be illustrated. The reaction temperature is usually    from room temperature to reflux temperature, and the reaction time    is usually from 1 hour to 1 day, varying based on a used starting    material, solvent and reaction temperature.-   (2) In case of pyrazolone derivatives represented by the above    general formula (V) wherein R³ is a halo(lower alkyl) group, a    corresponding compound represented by the above general    formula (VII) can be prepared by subjecting a corresponding    pyrazolone derivative represented by the above general formula (V)    to glycosidation using acetobromo-α-D-glucose in the presence of a    base such as potassium carbonate in an inert solvent, and subjecting    the resulting compound to N-alkylation using an alkylating agent    represented by the above general formula (VI) in the presence of a    base such as pottasium carbonate in an inert solvent as occasion    demands. As the solvent used in the glycosidation reaction,    acetonitrile, tetrohydrofuran and the like can be illustrated. The    reaction temperature is usually from room temperature to reflux    temperature, and the reaction time is usually from 1 hour to 1 day,    varying based on a used starting material, solvent and reaction    temperature. As the solvent used in the N-alkylation reaction,    acetonitrile, N,N-dimethylformamide, tetrohydrofuran, a mixed    solvent thereof and the like can be illustrated. The reaction    temperature is usually from room temperature to reflux temperature,    and the reaction time is usually from 1 hour to 1 day, varying based    on a used starting material, solvent and reaction temperature.

The obtained compounds represented by the above general formula (VII)can be also used in process 4 after converting into a salt thereof inusual way.

Process 4

A compound (I) of the present invention can be prepared by subjecting acompound represented by the above general formula (VII) to alkalinehydrolysis. As the solvent used in the reaction, methanol, ethanol,tetrahydrofuran, water, a mixed solvent thereof and the like can beillustrated, and as the base used, sodium hydroxide, sodium ethoxide andthe like can be illustrated. The reaction temperature is usually from 0°C. to room temperature, and the reaction time is usually from 30 minutesto 6 hours, varying based on a used starting material, solvent andreaction temperature.

Of the compounds represented by the above general formula (I), compoundswherein the substituent R¹ is a lower alkyl group can be preparedaccording to the following procedure:

wherein Q¹, R², R⁵, T¹ and X have the same meanings as defined above.Process 5

A compound represented by the above general formula (Ib) of the presentinvention can be prepared by subjecting a compound represented by theabove general formula (Ia) of the present invention to N-alkylationusing an N-alkylating agent represented by the above general formula(VI) in the presence of a base such as potassium carbonate or cesiumcarbonate, and occasionally a catalytic amount of sodium iodide in aninert solvent. As the inert solvent used in the reaction,N,N-dimethylformamide, dimethoxyethane, dimethyl sulfoxide,tetrahydrofuran, ethanol, a mixed solvent thereof and the like can beillustrated. The reaction temperature is usually from room temperatureto reflux temperature, and the reaction time is usually from 10 minutesto 1 day, varying based on a used starting material, solvent andreaction temperature.

The compounds represented by the above general formula (VII) and saltsthereof which are used in the aforementioned production process areuseful compounds as intermediates of compounds represented by the abovegeneral formula (I) of the present invention. In the compoundsrepresented by the above general formula (VII) as well as the compoundsrepresented by the above general formula (I) of the present invention,it is preferable that either of the substituents Q² and T² is astraight-chained or branched alkyl group having 1 to 3 carbon atoms, andit is more preferable that either of them is a methyl group.

In the compound represented by the above general formula (V) as startingmaterials, there are the following three tautomers, varying based on thechange of reaction conditions:

wherein R² and R³ have the same meanings as defined above. The compoundsrepresented by the above general formula (V) and salts thereof which areused in the aforementioned production process are useful compounds asintermediates of compounds represented by the above general formula (I)of the present invention. In the compounds represented by the abovegeneral formula (V) as well as the compounds represented by the abovegeneral formula (I) of the present invention, it is preferable that thesubstituent R³ is a straight-chained or branched alkyl group having 1 to3 carbon atoms, and it is more preferable that the substituent R³ is amethyl group.

The compounds represented by the above general formula (I) of thepresent invention obtained by the above production processes can beisolated and purified by conventional separation means such asfractional recrystallization, purification using chromatography andsolvent extraction.

The glucopyranosyloxypyrazole derivatives represented by the abovegeneral formula (I) of the present invention can be converted into theirpharmaceutically acceptable salts in the usual way. Examples of suchsalts include acid addition salts with mineral acids such ashydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,nitric acid, phosphoric acid and the like, acid addition salts withorganic acids such as formic acid, acetic acid, methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, citricacid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalicacid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid,glutamic acid, aspartic acid and the like, and salts with inorganicbases such as a sodium salt, a potassium salt and the like.

The compounds represented by the above general formula (I) of thepresent invention include their their solvates with pharmaceuticallyacceptable solvents such as ethanol and water.

The compounds represented by the above general formula (I) of thepresent invention have an excellent inhibitory activity in human SGLT2and are extremely useful as agents for the prevention or treatment ofdiabetes, diabetic complications, obesity and the like. For example, inthe following assay for inhibitory effect on human SGLT2 activity, thecompounds of the present invention exerted a potent inhibitory activityin human SGLT2. On the other hand, since WAY-123783 has an extremelyweak inhibitory activity in human SGLT2, it can not be expected to exertan enough effect as a human SGLT2 inhibitor.

When the pharmaceutical compositions of the present invention areemployed in the practical treatment, various dosage forms are useddepending on their uses. As examples of the dosage forms, powders,granules, fine granules, dry sirups, tablets, capsules, injections,solutions, ointments, suppositories, poultices and the like areillustrated, which are orally or parenterally administered.

These pharmaceutical compositions can be prepared by admixing with or bydiluting and dissolving an appropriate pharmaceutical additive such asexcipients, disintegrators, binders, lubricants, diluents, buffers,isotonicities, antiseptics, moistening agents, emulsifiers, dispersingagents, stabilizing agents, dissolving aids and the like, andformulating the mixture in accordance with the conventional manner.

When the pharmaceutical compositions of the present invention areemployed in the practical treatment, the dosage of a compoundrepresented by the above general formula (I) or a pharmaceuticallyacceptable salt thereof as the active ingredient is appropriatelydecided depending on the age, sex, body weight and degree of symptomsand treatment of each patient, which is approximately within the rangeof from 0.1 to 1,000 mg per day per adult human in the case of oraladministration and approximately within the range of from 0.01 to 300 mgper day per adult human in the case of parenteral administration, andthe daily dose can be divided into one to several doses per day andadministered suitably.

EXAMPLES

The present invention is further illustrated in more detail by way ofthe following Reference Examples, Examples and Test Examples. However,the present invention is not limited thereto.

Example 11,2-Dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one

To a solution of 4-isopropoxybenzylalcohol (0.34 g) in tetrahydrofuran(6 mL) were added triethylamine (0.28 mL) and methanesulfonyl chloride(0.16 mL), and the mixture was stirred at room temperature for 30minutes. The resulting insoluble material was removed by filtration. Theobtained solution of 4-isopropoxybenzyl methanesulfonate intetrahydrofuran was added to a suspension of sodium hydride (60%, 81 mg)and methyl acetoacetate (0.20 mL) in 1,2-dimethoxyethane (10 mL), andthe mixture was stirred at 80° C. overnight. The reaction mixture waspoured into a saturated aqueous sodium hydrogen carbonate solution, andthe resulting mixture was extracted with diethyl ether. The organiclayer was washed with brine and dried over anhydrous magnesium sulfate.The solvent was removed under reduced pressure, and the residue wasdissolved in toluene (5 mL). Anhydrous hydrazine (0.19 mL) was added tothe solution, and the mixture was stirred at 80° C. overnight. Thesolvent was removed under reduced pressure, and the residue was purifiedby column chromatography on silica gel (eluent:dichloromethane/methanol=10/1) to give1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one (95mg).

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.22 (6H, d, J=6.0 Hz), 1.99 (3H, s),3.45 (2H, s), 4.40–4.60 (1H, m), 6.65–6.80 (2H, m), 6.95–7.10 (2H, m)

Example 21,2-Dihydro-5-methyl-4-[(4-propylphenyl)methyl]-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inExample 1 using 4-propylbenzyl alcohol instead of 4-isopropoxybenzylalcohol.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 0.75–0.95 (3H, m), 1.45–1.65 (2H, m),1.99 (3H, s), 2.40–2.55 (2H, m), 3.32 (2H, s), 6.95–7.10 (4H, m)

Example 31,2-Dihydro-4-[(4-isobutylphenyl)methyl]-5-methyl-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inExample 1 using 4-isobutylbenzyl alcohol instead of 4-isopropoxybenzylalcohol.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 0.83 (6H, d, J=6.6 Hz), 1.70–1.85 (1H,m), 1.99 (3H, s), 2.30–2.45 (2H, m), 3.50 (2H, s), 6.90–7.10 (4H, m)

Example 41,2-Dihydro-5-methyl-4-[(4-propoxyphenyl)methyl]-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inExample 1 using 4-propoxybenzyl alcohol instead of 4-isopropoxybenzylalcohol.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 0.95 (3H, t, J=7.4 Hz), 1.60–1.75 (2H,m), 1.98 (3H, s), 3.46 (2H, s), 3.75–3.90 (2H, m), 6.70–6.85 (2H, m),6.95–7.10 (2H, m)

Example 54-[(4-Ethoxyphenyl)methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inExample 1 using 4-ethoxybenzyl alcohol instead of 4-isopropoxybenzylalcohol.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.20–1.35 (3H, m), 1.98 (3H, s), 3.46(2H, s), 3.85–4.05 (2H, m), 6.70–6.85 (2H, m), 6.95–7.10 (2H, m)

Example 61,2-Dihydro-5-methyl-4-[(4-trifluoromethylphenyl)methyl]-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inExample 1 using 4-trifluoromethylbenzyl alcohol instead of4-isopropoxybenzyl alcohol.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 2.02 (3H, s), 3.64 (2H, s), 7.30–7.45(2H, m), 7.55–7.70 (2H, m)

Example 74-[(4-tert-Butylphenyl)methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inExample 1 using 4-tert-butylbenzyl alcohol instead of 4-isopropoxybenzylalcohol.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.24 (9H, s), 2.01 (3H, s), 3.49 (2H,s), 7.00–7.15 (2H, m), 7.15–7.30 (2H, m)

Example 84-[(4-Butoxyphenyl)methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inExample 1 using 4-butoxybenzyl alcohol instead of 4-isopropoxybenzylalcohol.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 0.91 (3H, t, J=7.4 Hz), 1.30–1.50 (2H,m), 1.55–1.75 (2H, m), 1.98 (3H, s), 3.46 (2H, s), 3.80–3.95 (2H, m),6.70–6.85 (2H, m), 6.95–7.10 (2H, m)

Example 91,2-Dihydro-5-methyl-4-[(4-methylthiophenyl)methyl]-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inExample 1 using 4-(methylthio)benzyl alcohol instead of4-isopropoxybenzyl alcohol.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.99 (3H, s), 2.42 (3H, s), 3.50 (2H,s), 7.05–7.20 (4H, m)

Example 105-Ethyl-1,2-dihydro-4-[(4-methylthiophenyl)methyl]-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inExample 1 using 4-(methylthio)benzyl alcohol instead of4-isopropoxybenzyl alcohol and using methyl 3-oxopentanoate instead ofmethyl acetoacetate.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.02 (3H, t, J=7.6 Hz), 2.39 (2H, q,J=7.6 Hz), 2.42 (3H, s), 3.51 (2H, s), 7.05–7.20 (4H, m)

Example 111,2-Dihydro-4-[(4-isopropylphenyl)methyl]-5-methyl-3H-pyrazol-3-one

To a suspension of sodium hydride (60%, 40 mg) in 1,2-dimethoxyethane (1mL) were added methyl acetoacetate (0.11 mL), 4-isopropylbenzyl chloride(0.17 g) and a catalytic amount of sodium iodide, and the mixture wasstirred at 80° C. overnight. The reaction mixture was poured into asaturated aqueous sodium hydrogen carbonate solution, and the mixturewas extracted with diethyl ether. The organic layer was washed withbrine and dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure, and the residue was dissolved in toluene(1 mL). Anhydrous hydrazine (0.094 mL) was added to the solution, andthe mixture was stirred at 80° C. overnight. The solvent was removedunder reduced pressure, and the residue was purified by columnchromatography on silica gel (eluent: dichloromethane/methanol=10/1) togive 1,2-dihydro-4-[(4-isopropylphenyl)methyl]-5-methyl-3H-pyrazol-3-one(0.12 g).

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.16 (6H, d, J=6.9 Hz), 2.01 (3H, s),2.70–2.90 (1H, m), 3.49 (2H, s), 6.95–7.20 (4H, m)

Example 124-[(4-Ethylphenyl)methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inExample 11 using 4-ethylbenzyl chloride instead of 4-isopropylbenzylchloride.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.13 (3H, t, J=7.6 Hz), 2.00 (3H, s),2.45–2.60 (2H, m), 3.49 (2H, s), 7.00–7.15 (4H, m)

Example 131,2-Dihydro-5-methyl-4-[(4-methylphenyl)methyl]-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inExample 11 using 4-methylbenzyl bromide instead of 4-isopropylbenzylchloride.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.98 (3H, s), 2.23 (3H, s), 3.48 (2H,s), 6.95–7.10 (4H, m)

Reference Example 14-Benzyl-1,2-dihydro-5-trifluoromethyl-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inExample 11 using ethyl trifluoroacetoacetate instead of methylacetoacetate and using benzyl bromide instead of 4-isopropylbenzylchloride.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 3.73 (2H, s), 7.05–7.35 (5H, m),12.50–13.10 (1H, brs)

Example 141,2-Dihydro-4-[(4-methoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inExample 11 using 4-methoxybenzyl bromide instead of 4-isopropylbenzylchloride.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 1.99 (3H, s), 3.47 (2H, s), 3.69 (3H,s), 6.75–6.85 (2H, m), 7.00–7.10 (2H, m), 8.70–11.70 (2H, br)

Reference Example 2 4-Benzyl-1,2-dihydro-5-methyl-3H-pyrazol-3-one

The title compound was prepared in a similar manner to that described inExample 11 using benzyl bromide instead of 4-isopropylbenzyl chloride.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm: 2.00 (3H, s), 3.54 (2H, s), 7.05–7.30(5H, s)

Example 154-[(4-Isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole

To a suspension of1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one (46mg), acetobromo-α-D-glucose (99 mg) and 4A molecular sieves intetrahydrofuran (3 mL) was added silver carbonate (66 mg), and themixture was stirred under shading the light at 65° C. overnight. Thereaction mixture was purified by column chromatography on aminopropylsilica gel (eluent: tetrahydrofuran). Further purification bypreparative thin layer chromatography on silica gel (developing solvent:ethyl acetate/hexane=2/1) afforded4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole(42 mg).

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.25–1.35 (6H, m), 1.88 (3H, s), 2.01(3H, s), 2.03 (3H, s), 2.05 (3H, s), 2.10 (3H, s), 3.45–3.65 (2H, m),3.80–3.90 (1H, m), 4.13 (1H, dd, J=2.3, 12.4 Hz), 4.31 (1H, dd, J=4.0,12.4 Hz), 4.40–4.55 (1H, m), 5.15–5.35 (3H, m), 5.50–5.60 (1H, m),6.70–6.80 (2H, m), 6.95–7.05 (2H, m)

Example 165-Methyl-4-[(4-propylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 15 using1,2-dihydro-5-methyl-4-[(4-propylphenyl)methyl]-3H-pyrazol-3-one insteadof 1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 0.91 (3H, t, J=7.3 Hz), 1.50–1.65 (2H,m), 1.86 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.05 (3H, s), 2.10 (3H,s), 2.45–2.55 (2H, m), 3.55 (1H, d, J=15.8 Hz), 3.63 (1H, d, J=15.8 Hz),3.80–3.90 (1H, m), 4.13 (1H, dd, J=2.3, 12.4 Hz), 4.30 (1H, dd, J=3.9,12.4 Hz), 5.15–5.35 (3H, m), 5.50–5.60 (1H, m), 7.00–7.20 (4H, m)

Example 174-[(4-Isobutylphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 15 using1,2-dihydro-4-[(4-isobutylphenyl)methyl]-5-methyl-3H-pyrazol-3-oneinstead of1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 0.87 (6H, d, J=6.6 Hz), 1.70–1.85 (1H,m), 1.87 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.06 (3H, s), 2.10 (3H,s), 2.40 (2H, d, J=7.2 Hz), 3.56 (1H, d, J=15.8 Hz), 3.63 (1H, d, J=15.8Hz), 3.80–3.90 (1H, m), 4.14 (1H, dd, J=2.3, 12.4 Hz), 4.31 (1H, dd,J=4.0, 12.4 Hz), 5.15–5.35 (3H, m), 5.50–5.60 (1H, m), 6.95–7.10 (4H, m)

Example 185-Methyl-4-[(4-propoxyphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 15 using1,2-dihydro-5-methyl-4-[(4-propoxyphenyl)methyl]-3H-pyrazol-3-oneinstead of1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.01 (3H, t, J=7.4 Hz), 1.70–1.85 (2H,m), 1.89 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.06 (3H, s), 2.10 (3H,s), 3.53 (1H, d, J=15.7 Hz), 3.59 (1H, d, J=15.7 Hz), 3.80–3.95 (3H, m),4.14 (1H, dd, J=2.3, 12.4 Hz), 4.31 (1H, dd, J=4.0, 12.4 Hz), 5.15–5.35(3H, m), 5.50–5.60 (1H, m), 6.70–6.80 (2H, m), 6.95–7.10 (2H, m)

Example 194-[(4-Ethoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 15 using4-[(4-ethoxyphenyl)-methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-oneinstead of1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.38 (3H, t, J=7.0 Hz), 1.89 (3H, s),2.01 (3H, s), 2.03 (3H, s), 2.06 (3H, s), 2.10 (3H, s), 3.53 (1H, d,J=15.8 Hz), 3.59 (1H, d, J=15.8 Hz), 3.80–3.90 (1H, m), 3.98 (2H, q,J=7.0 Hz), 4.13 (1H, dd, J=2.3, 12.4 Hz), 4.31 (1H, dd, J=4.0, 12.4),5.15–5.30 (3H, m), 5.50–5.60 (1H, m), 6.70–6.80 (2H, m), 6.95–7.10 (2H,m)

Example 205-Methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-trifluoromethylphenyl)methyl]-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 15 using1,2-dihydro-5-methyl-4-[(4-trifluoromethylphenyl)methyl]-3H-pyrazol-3-oneinstead of1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.85 (3H, s), 2.01 (3H, s), 2.03 (3H, s),2.06 (3H, s), 2.14 (3H, s), 3.65 (1H, d, J=15.9 Hz), 3.71 (1H, d, J=15.9Hz), 3.80–3.90 (1H, m), 4.14 (1H, dd, J=2.4, 12.4 Hz), 4.31 (1H, dd,J=4.0, 12.4 Hz), 5.15–5.40 (3H, m), 5.55–5.65 (1H, m), 7.20–7.30 (2H,m), 7.45–7.55 (2H, m)

Example 214-[(4-tert-Butylphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 15 using4-[(4-tert-butylphenyl)-methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-oneinstead of1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.27 (9H, s), 1.84 (3H, s), 2.01 (3H, s),2.03 (3H, s), 2.06 (3H, s), 2.14 (3H, s), 3.56 (1H, d, J=15.8 Hz), 3.64(1H, d, J=15.8 Hz), 3.80–3.90 (1H, m), 4.13 (1H, dd, J=2.3, 12.4 Hz),4.31 (1H, dd, J=4.0, 12.4 Hz), 5.15–5.30 (3H, m), 5.50–5.60 (1H, m),7.00–7.10 (2H, m), 7.20–7.30 (2H, m)

Example 224-[(4-Butoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 15 using4-[(4-butoxyphenyl)methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-one insteadof1,2-dihydro-4-[(4-isopropoxyphenyl)-methyl]-5-methyl-3H-pyrazol-3-one.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 0.96 (3H, t, J=7.4 Hz), 1.40–1.55 (2H,m), 1.65–1.80 (2H, m), 1.88 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.06(3H, s), 2.10 (3H, s), 3.52 (1H, d, J=15.8 Hz), 3.59 (1H, d, J=15.8 Hz),3.80–3.90 (1H, m), 3.91 (2H, t, J=6.5 Hz), 4.13 (1H, dd, J=2.3, 12.4Hz), 4.31 (1H, dd, J=4.0, 12.4 Hz), 5.15–5.30 (3H, m), 5.50–5.60 (1H,m), 6.70–6.80 (2H, m), 6.95–7.10 (2H, m)

Example 235-Methyl-4-[(4-methylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 15 using1,2-dihydro-5-methyl-4-[(4-methylthiophenyl)methyl]-3H-pyrazol-3-oneinstead of1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.88 (3H, s), 2.01 (3H, s), 2.03 (3H, s),2.07 (3H, s), 2.12 (3H, s), 2.44 (3H, s), 3.50–3.65 (2H, m), 3.80–3.90(1H, m), 4.13 (1H, dd, J=2.4, 12.4 Hz), 4.31 (1H, dd, J=4.1, 12.4 Hz),5.15–5.30 (3H, m), 5.55–5.65 (1H, m), 7.00–7.10 (2H, m), 7.10–7.20 (2H,m), 8.65–8.85 (1H, brs)

Example 245-Ethyl-4-[(4-methylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 15 using5-ethyl-1,2-dihydro-4-[(4-methylthiophenyl)methyl]-3H-pyrazol-3-oneinstead of1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.13 (3H, t, J=7.6 Hz), 1.88 (3H, s),2.01 (3H, s), 2.03 (3H, s), 2.06 (3H, s), 2.44 (3H, s), 2.45–2.55 (2H,m), 3.50–3.70 (2H, m), 3.80–3.90 (1H, m), 4.05–4.20 (1H, m), 4.31 (1H,dd, J=4.0, 12.4 Hz), 5.15–5.35 (3H, m), 5.55–5.65 (1H, m), 7.00–7.10(2H, m), 7.10–7.20 (2H, m), 8.80–9.20 (1H, brs)

Example 254-[(4-Isopropylphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 15 using1,2-dihydro-4-[(4-isopropylphenyl)methyl]-5-methyl-3H-pyrazol-3-oneinstead of1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.20 (6H, d, J=6.9 Hz), 1.85 (3H, s),2.01 (3H, s), 2.03 (3H, s), 2.06 (3H, s), 2.13 (3H, s), 2.75–2.90 (1H,m), 3.56 (1H, d, J=15.8 Hz), 3.63 (1H, d, J=15.8 Hz), 3.80–3.90 (1H, m),4.05–4.20 (1H, m), 4.31 (1H, dd, J=4.0, 12.4 Hz), 5.15–5.35 (3H, m),5.50–5.60 (1H, m), 7.00–7.15 (4H, m), 8.70–9.30 (1H, brs)

Example 264-[(4-Methylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole

To a solution of1,2-dihydro-4-[(4-methylthiophenyl)methyl]-5-trifluoromethyl-3H-pyrazol-3-one(2.0 g) in acetonitrile (100 mL) were added acetobromo-α-D-glucose (3.1g) and potassium carbonate (1.1 g), and the mixture was stirred at roomtemperature overnight. Water was added to the reaction mixture, and theresulting mixture was extracted with ethyl acetate. The organic layerwas washed with a saturated aqueous sodium hydrogen carbonate solutionand brine, and dried over anhydrous magnesium sulfate. The solvent wasremoved under reduced pressure, and the residue was purified by columnchromatography on silica gel (eluent: hexane/ethyl acetate=1/1) to give4-[(4-methylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole(2.0 g).

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.91 (3H, s), 2.03 (3H, s), 2.04 (3H, s),2.09 (3H, s), 2.45 (3H, s), 3.73 (2H, s), 3.75–3.90 (1H, m), 4.15–4.35(2H, m), 5.15–5.65 (4H, m), 7.00–7.20 (4H, m)

Example 274-Benzyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 26 using 4-benzyl-1,2-dihydro-5-trifluoromethyl-3H-pyrazol-3-oneinstead of1,2-dihydro-4-[(4-methylthiophenyl)methyl]-5-trifluoromethyl-3H-pyrazol-3-one.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.89 (3H, s), 2.02 (3H, s), 2.04 (3H, s),2.08 (3H, s), 3.70–3.90 (3H, m), 4.15–4.30 (2H, m), 5.10–5.50 (4H, m),7.10–7.30 (5H, m)

Example 284-[(4-Methoxyphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 26 using1,2-dihydro-4-[(4-methoxyphenyl)methyl]-5-trifluoromethyl-3H-pyrazol-3-oneinstead of1,2-dihydro-4-[(4-methylthiophenyl)methyl]-5-trifluoromethyl-3H-pyrazol-3-one.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.93 (3H, s), 2.03 (3H, s), 2.05 (3H, s),2.09 (3H, s), 3.65–3.75 (2H, m), 3.77 (3H, s), 3.75–3.90 (1H, m),4.15–4.35 (2H, m), 5.10–5.45 (4H, m), 6.75–6.85 (2H, m), 7.00–7.15 (2H,m)

Example 294-[(4-Methoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 15 using1,2-dihydro-4-[(4-methoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-oneinstead of1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.89 (3H, s), 2.02 (3H, s), 2.03 (3H, s),2.05 (3H, s), 2.10 (3H, s), 3.45–3.65 (2H, m), 3.76 (3H, s), 3.80–3.90(1H, m), 4.11 (1H, dd, J=2.2, 12.4 Hz), 4.30 (1H, dd, J=4.0, 12.4 Hz),5.15–5.35 (3H, m), 5.50–5.60 (1H, m), 6.70–6.85 (2H, m), 7.00–7.10 (2H,m)

Example 304-Benzyl-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 15 using 4-benzyl-1,2-dihydro-5-methyl-3H-pyrazol-3-one insteadof 1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one.

¹H-NMR (400 MHz, CDCl₃) δ ppm: 1.86 (3H, s), 2.01 (3H, s), 2.03 (3H, s),2.06 (3H, s), 2.11 (3H, s), 3.59 (1H, d, J=15.8 Hz), 3.66 (1H, d, J=15.8Hz), 3.80–3.90 (1H, m), 4.11 (1H, dd, J=2.3, 12.4 Hz), 4.30 (1H, dd,J=4.0, 12.4 Hz), 5.15–5.30 (3H, m), 5.50–5.65 (1H, m), 7.05–7.30 (5H,m), 8.75–9.55 (1H, brs)

Example 314-[(4-Methoxyphenyl)methyl]-1,5-dimethyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)pyrazole

A suspension of4-[(4-methoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole(18 mg), potassium carbonate (14 mg) and iodomethane (4.7 mg) inacetonitrile (2 mL) was stirred at 75° C. overnight. The reactionmixture was filtered through celite®, and the solvent of the filtratewas removed under reduced pressure. The residue was purified bypreparative thin layer chromatography (developing solvent:benzene/acetone=2/1) to give4-[(4-methoxyphenyl)methyl]-1,5-dimethyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)pyrazole(4 mg).

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.90 (3H, s), 2.01 (3H, s), 2.03 (3H, s),2.06 (3H, s), 2.07 (3H, s), 3.45–3.60 (2H, m), 3.60 (3H, s), 3.76 (3H,s), 3.80–3.90 (1H, m), 4.13 (1H, dd, J=2.4, 12.4 Hz), 4.29 (1H, dd,J=4.1, 12.4 Hz), 5.15–5.30 (3H, m), 5.50–5.60 (1H, m), 6.70–6.80 (2H,m), 7.00–7.10 (2H, m)

Example 321-Methyl-4-[(4-methylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethylpyrazole

A suspension of4-[(4-metylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole(30 mg), potassium carbonate (8.0 mg) and iodomethane (8.2 mg) intetrahydrofuran (1 mL) was stirred at 75° C. overnight. The reactionmixture was filtered through celite®, and the solvent of the filtratewas removed under reduced pressure. The residue was purified bypreparative thin layer chromatography (developing solvent:dichloromethane/ethyl acetate=5/1) to give1-methyl-4-[(4-methylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethylpyrazole(13 mg).

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.89 (3H, s), 2.02 (3H, s), 2.04 (3H, s),2.07 (3H, s), 2.44 (3H, s), 3.65–3.95 (6H, m), 4.14 (1H, dd. J=2.3, 12.4Hz), 4.29 (1H, dd, J=4.3, 12.4 Hz), 5.15–5.35 (3H, m), 5.50–5.65 (1H,m), 7.00–7.20 (4H, m)

Example 331-Ethyl-4-[(4-methylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethylpyrazole

The title compound was prepared in a similar manner to that described inExample 32 using iodoethane instead of iodomethane.

¹H-NMR (500 MHz, CDCl₃) δ ppm: 1.40 (3H, t, J=7.2 Hz), 1.90 (3H, s),2.02 (3H, s), 2.04 (3H, s), 2.06 (3H, s), 2.44 (3H, s), 3.72 (2H, s),3.80–3.90 (1H, m), 4.05–4.20 (3H, m), 4.27 (1H, dd, J=4.5, 12.4 Hz),5.10–5.35 (3H, m), 5.55–5.65 (1H, m), 7.00–7.10 (2H, m), 7.10–7.20 (2H,m)

Example 344-[(4-Methylthiophenyl)methyl]-1-propyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethylpyrazole

The title compound was prepared in a similar manner to that described inExample 32 using iodopropane instead of iodomethane.

¹H-NMR (500 MHZ, CDCl₃) δ ppm: 0.92 (3H, t, J=7.4 Hz), 1.75–1.90 (2H,m), 1.89 (3H, s), 2.02 (3H, s), 2.04 (3H, s), 2.06 (3H, s), 2.44 (3H,s), 3.72 (2H, s), 3.80–3.90 (1H, m), 3.90–4.05 (2H, m), 4.12 (1H, dd,J=2.3, 12.4 Hz), 4.27 (1H, dd, J=4.5, 12.4 Hz), 5.10–5.35 (3H, m),5.55–5.65 (1H, m), 7.00–7.10 (2H, m), 7.10–7.20 (2H, m)

Example 353-(β-D-Glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole

To a solution of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole(61 mg) in ethanol (3 mL) was added 1N aqueous sodium hydroxide solution(0.53 mL), and the mixture was stirred at room temperature for 2 hours.The solvent was removed under reduced pressure, and the residue waspurified by solid phase extraction on ODS (washing solvent: distilledwater, eluent: methanol) to give3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole(39 mg).

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.26 (6H, d, J=5.9 Hz), 2.05 (3H, s),3.25–3.45 (4H, m), 3.55–3.75 (3H, m), 3.75–3.90 (1H, m), 4.45–4.60 (1H,m), 5.00–5.10 (1H, m), 6.70–6.80 (2H, m), 7.00–7.15 (2H, m)

Example 363-(β-D-Glucopyranosyloxy)-5-methyl-4-[(4-propylphenyl)methyl]-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 35 using5-methyl-4-[(4-propylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 0.91 (3H, t, J=7.5 Hz), 1.50–1.65 (2H,m), 2.05 (3H, s), 2.45–2.60 (2H, m), 3.25–3.45 (4H, m), 3.55–3.75 (3H,m), 3.83 (1H, d, J=11.9 Hz), 5.00–5.10 (1H, m), 7.00–7.15 (4H, m)

Example 373-(β-D-Glucopyranosyloxy)-4-[(4-isobutylphenyl)methyl]-5-methyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 35 using4-[(4-isobutylphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 0.87 (6H, d, J=6.6 Hz), 1.70–1.90 (1H,m), 2.04 (3H, s), 2.41 (2H, d, J=7.1 Hz), 3.25–3.45 (4H, m), 3.55–3.90(4H, m), 5.00–5.10 (1H, m), 6.95–7.15 (4H, m)

Example 383-(β-D-Glucopyranosyloxy)-5-methyl-4-[(4-propoxyphenyl)methyl]-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 35 using5-methyl-4-[(4-propoxyphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.02 (3H, t, J=7.4 Hz), 1.65–1.80 (2H,m), 2.05 (3H, s), 3.25–3.45 (4H, m), 3.60–3.75 (3H, m), 3.80–3.90 (3H,m), 5.00–5.10 (1H, m), 6.70–6.85 (2H, m), 7.05–7.15 (2H, m)

Example 394-[(4-Ethoxyphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 35 using4-[(4-ethoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.34 (3H, t, J=7.0 Hz), 2.05 (3H, s),3.25–3.45 (4H, m), 3.60–3.75 (3H, m), 3.80–3.90 (1H, m), 3.97 (2H, q,J=7.0 Hz), 5.00–5.10 (1H, m), 6.70–6.85 (2H, m), 7.05–7.15 (2H, m)

Example 403-(β-Glucopyranosyloxy)-5-methyl-4-[(4-trifluoromethylphenyl)-methyl]-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 35 using5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-trifluoromethylphenyl)methyl]-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 2.08 (3H, s), 3.20–3.40 (4H, m), 3.67(1H, dd, J=5.0, 11.9 Hz), 3.75–3.90 (3H, m), 5.00–5.10 (1H, m),7.30–7.45 (2H, m), 7.45–7.60 (2H, m)

Example 414-[(4-tert-Butylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 35 using4-[(4-tert-butylphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.28 (9H, s), 2.06 (3H, s), 3.25–3.45(4H, m), 3.60–3.90 (4H, m), 5.00–5.10 (1H, m), 7.05–7.15 (2H, m),7.20–7.30 (2H, m)

Example 424-[(4-Butoxyphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 35 using4-[(4-butoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 0.97 (3H, t, J=7.4 Hz), 1.40–1.55 (2H,m), 1.65–1.80 (2H, m), 2.05 (3H, s), 3.30–3.45 (4H, m), 3.60–3.75 (3H,m), 3.83 (1H, d, J=12.0 Hz), 3.91 (2H, t, J=6.4 Hz), 5.00–5.10 (1H, m),6.70–6.85 (2H, m), 7.05–7.15 (2H, m)

Example 433-(β-D-Glucopyranosyloxy)-5-methyl-4-[(4-methylthiophenyl)methyl]-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 35 using5-methyl-4-[(4-methylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 2.06 (3H, s), 2.42 (3H, s), 3.20–3.45(4H, m), 3.55–3.75 (3H, m), 3.80–3.90 (1H, m), 5.00–5.10 (1H, m),7.05–7.20 (4H, m)

Example 445-Ethyl-3-(β-D-glucopyranosyloxy)-4-[(4-methylthiophenyl)methyl]-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 35 using5-ethyl-4-[(4-methylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.06 (3H, t, J=7.6 Hz), 2.42 (3H, s),2.47 (2H, q, J=7.6 Hz), 3.25–3.45 (4H, m), 3.60–3.80 (3H, m), 3.80–3.90(1H, m), 5.00–5.10 (1H, m), 7.10–7.20 (4H, m)

Example 453-(β-D-Glucopyranosyloxy)-4-[(4-isopropylphenyl)methyl]-5-methyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 35 using4-[(4-isopropylphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.20 (6H, d, J=6.9 Hz), 2.05 (3H, s),2.75–2.90 (1H, m), 3.25–3.45 (4H, m), 3.55–3.90 (4H, m), 5.00–5.10 (1H,m), 7.00–7.15 (4H, m)

Example 463-(β-D-Glucopyranosyloxy)-4-[(4-methylthiophenyl)methyl]-5-trifluoromethyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 35 using4-[(4-methylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-5-trifluoromethyl-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 2.42 (3H, s), 3.25–3.50 (4H, m), 3.69(1H, dd, J=4.9, 12.0 Hz), 3.75–3.90 (3H, m), 4.90–5.10 (1H, m),7.10–7.20 (4H, m)

Example 474-Benzyl-3-(β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 35 using4-benzyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 3.25–3.45 (4H, m), 3.67 (1H, dd, J=5.3,12.0 Hz), 3.80–3.95 (3H, m), 4.97 (1H, d, J=7.4 Hz), 7.05–7.25 (5H, m)

Example 483-(β-D-Glucopyranosyloxy)-4-[(4-methoxyphenyl)methyl]-5-trifluoromethyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 35 using4-[(4-methoxyphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-5-trifluoromethyl-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 3.25–3.45 (4H, m), 3.67 (1H, d, J=5.4,12.1 Hz), 3.73 (3H, s), 3.75–3.90 (3H, m), 4.90–5.00 (1H, m), 6.70–6.85(2H, m), 7.05–7.15 (2H, m)

Example 493-(β-D-Glucopyranosyloxy)-4-[(4-methoxyphenyl)methyl]-5-methyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 35 using4-[(4-methoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 2.04 (3H, s), 3.25–3.45 (4H, m),3.55–3.75 (3H, m), 3.73 (3H, s), 3.80–3.90 (1H, m), 5.00–5.10 (1H, m),6.75–6.85 (2H, m), 7.05–7.15 (2H, m)

Example 50 4-Benzyl-3-(β-D-glucopyranosyloxy)-5-methyl-1H-pyrazole

The title compound was prepared in a similar manner to that described inExample 35 using4-benzyl-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 2.05 (3H, s), 3.25–3.45 (4H, m),3.60–3.90 (4H, m), 5.00–5.10 (1H, m), 7.05–7.25 (5H, m)

Example 513-(β-D-Glucopyranosyloxy)-4-[(4-methoxyphenyl)methyl]-1,5-dimethylpyrazole

The title compound was prepared in a similar manner to that described inExample 35 using4-[(4-methoxyphenyl)methyl]-1,5-dimethyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 2.06 (3H, s), 3.25–3.45 (4H, m),3.55–3.70 (6H, m), 3.73 (3H, s), 3.75–3.90 (1H, m), 5.00–5.10 (1H, m),6.70–6.80 (2H, m), 7.05–7.15 (2H, m)

Example 523-(β-D-Glucopyranosyloxy)-1-methyl-4-[(4-methylthiophenyl)methyl]-5-trifluoromethylpyrazole

The title compound was prepared in a similar manner to that described inExample 35 using1-methyl-4-[(4-methylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethylpyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 2.42 (3H, s), 3.30–3.50 (4H, m), 3.69(1H, dd, J=4.7, 12.0 Hz), 3.75–3.90 (6H, m), 5.25–5.35 (1H, m),7.05–7.20 (4H, m)

Example 531-Ethyl-3-(β-D-glucopyranosyloxy)-4-[(4-methylthiophenyl)methyl]-5-trifluoromethylpyrazole

The title compound was prepared in a similar manner to that described inExample 35 using1-ethyl-4-[(4-methylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethylpyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.38 (3H, t, J=7.1 Hz), 2.42 (3H, s),3.30–3.50 (4H, m), 3.60–3.75 (1H, m), 3.75–3.90 (1H, m), 4.14 (2H, q,J=7.1 Hz), 5.25–5.35 (1H, m), 7.05–7.20 (4H, m)

Example 543-(β-D-Glucopyranosyloxy)-4-[(4-methylthiophenyl)methyl]-1-propyl-5-trifluoromethylpyrazole

The title compound was prepared in a similar manner to that described inExample 35 using4-[(4-methylthiophenyl)methyl]-1-propyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethylpyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 0.90 (3H, t, J=7.4 Hz), 1.75–1.90 (2H,m), 2.42 (3H, s), 3.30–3.50 (4H, m), 3.69 (1H, dd, J=4.9, 12.0 Hz),3.75–3.90 (3H, m), 4.00–4.10 (2H, m), 5.25–5.35 (1H, m), 7.05–7.20 (4H,m)

Example 553-(β-D-Glucopyranosyloxy)-5-methyl-4-[(4-methylphenyl)methyl]-1H-pyrazole

5-Methyl-4-[(4-methylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazolewas prepared in a similar manner to that described in Example 15 using1,2-dihydro-5-methyl-4-[(4-methylphenyl)methyl]-3H-pyrazol-3-one insteadof 1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one.Then, the title compound was prepared in a similar manner to thatdescribed in Example 35 using5-methyl-4-[(4-methylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 2.04 (3H, s), 2.26 (3H, s), 3.25–3.45(4H, m), 3.55–3.90 (4H, m), 5.00–5.10 (1H, m), 6.95–7.15 (4H, m)

Example 564-[(4-Ethylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methyl-1H-pyrazole

4-[(4-Ethylphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazolewas prepared in a similar manner to that described in Example 15 using4-[(4-ethylphenyl)methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-one insteadof 1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one.Then, the title compound was prepared in a similar manner to thatdescribed in Example 35 using4-[(4-ethylphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.18 (3H, t, J=7.6 Hz), 2.04 (3H, s),2.57 (2H, q, J=7.6 Hz), 3.25–3.45 (4H, m), 3.55–3.90 (4H, m), 5.00–5.10(1H, m), 6.95–7.20 (4H, m)

Example 573-(β-D-Glucopyranosyloxy)-4-[(4-methylphenyl)methyl]-5-trifluoromethyl-1H-pyrazole

4-[(4-Methylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazolewas prepared in a similar manner to that described in Example 26 using1,2-dihydro-4-[(4-methylphenyl)methyl]-5-trifluoromethyl-3H-pyrazol-3-oneinstead of1,2-dihydro-4-[(4-methylthiophenyl)methyl]-5-trifluoromethyl-3H-pyrazol-3-one.Then, the title compound was prepared in a similar manner to thatdescribed in Example 35 using4-[(4-methylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 2.25 (3H, s), 3.20–3.45 (4H, m),3.55–3.70 (1H, m), 3.70–3.90 (3H, m), 4.80–4.95 (1H, m), 6.90–7.15 (4H,m)

Example 584-[(4-Ethylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole

4-[(4-Ethylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazolewas prepared in a similar manner to that described in Example 26 using4-[(4-ethylphenyl)methyl]-1,2-dihydro-5-trifluoromethyl-3H-pyrazol-3-oneinstead of1,2-dihydro-4-[(4-methylthiophenyl)methyl]-5-trifluoromethyl-3H-pyrazol-3-one.Then, the title compound was prepared in a similar manner to thatdescribed in Example 35 using4-[(4-ethylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.18 (3H, t, J=7.6 Hz), 2.50–2.60 (2H,m), 3.15–3.40 (4H, m), 3.55–3.65 (1H, m), 3.70–3.90 (3H, m), 4.80–4.95(1H, m), 6.95–7.15 (4H, m)

Example 593-(β-D-Glucopyranosyloxy)-4-[(4-isopropylphenyl)methyl]-5-trifluoromethyl-1H-pyrazole

4-[(4-Isopropylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazolewas prepared in a similar manner to that described in Example 26 using1,2-dihydro-4-[(4-isopropylphenyl)methyl]-5-trifluoromethyl-3H-pyrazol-3-oneinstead of1,2-dihydro-4-[(4-methylthiophenyl)methyl]-5-trifluoro-methyl-3H-pyrazol-3-one.Then, the title compound was prepared in a similar manner to thatdescribed in Example 35 using4-[(4-isopropylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.20 (6H, d, J=6.9 Hz), 2.75–2.85 (1H,m), 3.15–3.40 (4H, m), 3.55–3.65 (1H, m), 3.70–3.90 (3H, m), 4.80–4.95(1H, m), 7.00–7.15 (4H, m)

Example 604-[(4-Chlorophenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole

4-[(4-Chlorophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazolewas prepared in a similar manner to that described in Example 26 using4-[(4-chlorophenyl)methyl]-1,2-dihydro-5-trifluoromethyl-3H-pyrazol-3-oneinstead of1,2-dihydro-4-[(4-methylthiophenyl)methyl]-5-trifluoromethyl-3H-pyrazol-3-one.Then, the title compound was prepared in a similar manner to thatdescribed in Example 35 using4-[(4-chlorophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazoleinstead of4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 3.20–3.40 (4H, m), 3.55–3.70 (1H, m),3.75–3.90 (3H, m), 4.80–4.95 (1H, m), 7.10–7.25 (4H, m)

Example 613-(β-D-Glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1-propylpyrazole

To a suspension of3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole(50 mg) and cesium carbonate (0.20 g) in N,N-dimethylformamide (1 mL)was added iodopropane (0.036 mL) at 50%, and the mixture was stirredovernight. Water was added to the reaction mixture, and the resultingmixture was purified by solid phase extraction on ODS (washing solvent:distilled water, eluent: methanol). The resulting semi-purified materialwas purified by column chromatography on silica gel (eluent:dichloromethane/methanol=8/1) to give3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1-propylpyrazole(28 mg).

¹H-NMR (500 MHz, CD₃OD) δ ppm: 0.87 (3H, t, J=7.4 Hz), 1.26 (6H, d,J=6.0 Hz), 1.65–1.80 (2H, m), 2.07 (3H, s), 3.25–3.45 (4H, m), 3.55–3.75(3H, m), 3.75–3.95 (3H, m), 4.40–4.60 (1H, m), 5.00–5.10 (1H, m),6.70–6.80 (2H, m), 7.00–7.10 (2H, m)

Example 621-Ethyl-3-(β-D-glucopyranosyloxy)-4-[(4-isopropylphenyl)methyl]-5-methylpyrazole

The title compound was prepared in a similar manner to that described inExample 61 using iodoethane instead of iodpropane.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.26 (6H, d, J=6.0 Hz), 1.29 (3H, t,J=7.2 Hz), 2.08 (3H, s), 3.25–3.45 (4H, m), 3.55–3.75 (3H, m), 3.75–3.90(1H, m), 3.96 (2H, q, J=7.2 Hz), 4.40–4.60 (1H, m), 5.00–5.10 (1H, m),6.70–6.80 (2H, m), 7.00–7.10 (2H, m)

Example 631-Ethyl-3-(β-D-glucopyranosyloxy)-4-[(4-methoxyphenyl)methyl]-5-methylpyrazole

The title compound was prepared in a similar manner to that described inExample 61 using3-(β-D-glucopyranosyloxy)-4-[(4-methoxyphenyl)methyl]-5-methyl-1H-pyrazoleinstead of3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazoleand using iodoethane instead of iodpropane.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.29 (3H, t, J=7.1 Hz), 2.07 (3H, s),3.20–3.45 (4H, m), 3.55–3.75 (6H, m), 3.82 (1H, dd, J=2.0, 12.0 Hz),3.90–4.05 (2H, m), 5.00–5.10 (1H, m), 6.70–6.85 (2H, m), 7.05–7.15 (2H,m)

Example 643-(β-D-Glucopyranosyloxy)-4-[(4-methoxyphenyl)methyl]-5-methyl-1-propylpyrazole

The title compound was prepared in a similar manner to that described inExample 61 using3-(β-D-glucopyranosyloxy)-4-[(4-methoxyphenyl)methyl]-5-methyl-1H-pyrazoleinstead of3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 0.87 (3H, t, J=7.5 Hz), 1.65–1.80 (2H,m), 2.07 (3H, s), 3.35–3.45 (4H, m), 3.60–3.75 (3H, m), 3.73 (3H, s),3.75–3.85 (1H, m), 3.85–3.95 (2H, m), 5.00–5.10 (1H, m), 6.70–6.85 (2H,m), 7.00–7.15 (2H, m)

Example 651-Ethyl-4-[(4-ethoxyphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methylpyrazole

The title compound was prepared in a similar manner to that described inExample 61 using4-[(4-ethoxyphenyl)methyl]-5-methyl-3-(β-D-glucopyranosyloxy)-1H-pyrazoleinstead of3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazoleand using iodoethane instead of iodopropane.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.28 (3H, t, J=7.4 Hz), 1.34 (3H, t,J=7.2 Hz), 2.07 (3H, s), 3.25–3.45 (4H, m), 3.55–3.75 (3H, m), 3.75–3.85(1H, m), 3.90–4.00 (4H, m), 5.00–5.10 (1H, m), 6.70–6.85 (2H, m),7.00–7.15 (2H, m)

Example 664-[(4-Ethoxyphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methyl-1-propylpyrazole

The title compound was prepared in a similar manner to that described inExample 61 using4-[(4-ethoxyphenyl)methyl]-5-methyl-3-(β-D-glucopyranosyloxy)-1H-pyrazoleinstead of3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 0.87 (3H, t, J=7.6 Hz), 1.34 (3H, t,J=7.1 Hz), 1.65–1.80 (2H, m), 2.07 (3H, s), 3.25–3.45 (4H, m), 3.55–3.75(3H, m), 3.81 (1H, dd, J=2.1, 12.1 Hz), 3.85–4.05 (4H, m), 5.00–5.10(1H, m), 6.70–6.85 (2H, m), 7.00–7.15 (2H, m)

Example 671-Ethyl-4-[(4-ethylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methylpyrazole

The title compound was prepared in a similar manner to that described inExample 61 using4-[(4-ethylphenyl)methyl]-5-methyl-3-(β-D-glucopyranosyloxy)-1H-pyrazoleinstead of3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazoleand using iodoethane instead of iodopropane.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.17 (3H, t, J=7.6 Hz), 1.28 (3H, t,J=7.2 Hz), 2.06 (3H, s), 2.56 (2H, q, J=7.6 Hz), 3.25–3.45 (4H, m),3.55–3.75 (3H, m), 3.75–3.85 (1H, m), 3.90–4.00 (2H, m), 5.00–5.10 (1H,m), 7.00–7.15 (4H, m)

Example 684-[(4-Ethylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methyl-1-propylpyrazole

The title compound was prepared in a similar manner to that described inExample 61 using4-[(4-ethylphenyl)methyl]-5-methyl-3-(β-D-glucopyranosyloxy)-1H-pyrazoleinstead of3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyhenyl)methyl]-5-methyl-1H-pyrazole.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 0.87 (3H, t, J=7.4 Hz), 1.17 (3H, t,J=7.6 Hz), 1.65–1.80 (2H, m), 2.06 (3H, s), 2.56 (2H, q, J=7.6 Hz),3.25–3.45 (4H, m), 3.60–3.95 (6H, m), 5.00–5.10 (1H, m), 7.00–7.15 (4H,m)

Example 691-Butyl-3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methylpyrazole

The title compound was prepared in a similar manner to that described inExample 61 using bromobutane instead of iodpropane.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 0.92 (3H, t, J=7.4 Hz), 1.20–1.40 (8H,m), 1.60–1.75 (2H, m), 2.07 (3H, s), 3.25–3.45 (4H, m), 3.55–3.75 (3H,m), 3.81 (1H, dd, J=2.1, 12.0 Hz), 3.91 (2H, t, J=7.2 Hz), 4.45–4.55(1H, m), 5.00–5.10 (1H, m), 6.70–6.80 (2H, m), 7.00–7.10 (2H, m)

Example 703-(β-D-Glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-1-isopropyl-5-methylpyrazole

The title compound was prepared in a similar manner to that described inExample 61 using 2-bromopropane instead of iodopropane.

¹H-NMR (500 MHz, CD₃OD) δ ppm: 1.26 (6H, d, J=6.0 Hz), 1.30–1.40 (6H,m), 2.08 (3H, s), 3.15–3.45 (4H, m), 3.55–3.75 (3H, m), 3.78 (1H, dd,J=2.3, 12.0 Hz), 4.35–4.45 (1H, m), 4.45–4.55 (1H, m), 5.00–5.10 (1H,m), 6.70–6.80 (2H, m), 7.00–7.10 (2H, m)

Test Example 1

Assay for Inhibitory Effect on Human SGLT2 Activity

-   1) Construction of the Plasmid Vector Expressing Human SGLT2

Preparation of the cDNA library for PCR amplification was performed byreverse transcription of a total RNA deprived from human kidney (Origene) with oligo dT as the primer, using Super Script preamplificationsystem (Gibco-BRL: LIFE TECHNOLOGIES). The DNA fragment coding for humanSGLT2 was amplified by the PCR reaction, in which the human kidney cDNAlibrary described above was used as the template and the following oligonucleotides 0702F and 0712R, presented as sequence number 1 and 2respectively, were used as the primers. The amplified DNA fragment wasligated into pCR (Invitrogen), a vector for cloning, according tostandard method of the kit. The Escherichia coli HB101 was transformedaccording to usual method and then selection of the transformants wasperformed on the LB agar medium containing 50 μg/mL of kanamycin. Afterplasmid DNA was extracted and purified from the one of thetransformants, amplifying of the DNA fragment coding for human SGLT2 wasperformed by the PCR reaction, in which the following oligo nucleotides0714F and 0715R, presented as sequence number 3 and 4 respectively, wereused as the primers. The amplified DNA fragment was digested withrestriction enzymes, Xho I and Hind III, and then purified with Wizardpurification System (Promega). This purified DNA fragment was insertedat into the corresponding restriction sites of pcDNA3.1 (−) Myc/His-B(Invitrogen), a vector for expressing of fusion protein. The Escherichiacoli HB101 was transformed according to usual method and then selectionof the transformant was performed on the LB agar medium containing 50μg/mL of ampicillin. After plasmid DNA was extracted and purified fromthis transformant, the base sequence of the DNA fragment inserted at themulti-cloning sites of the vector pcDNA3.1 (−) Myc/His-B was analyzed.This clone had a single base substitution (ATC which codes for theisoleucine-433 was substituted by GTC) compared with the human SGLT2reported by Wells et al (Am. J. Physiol., Vol. 263, pp. 459–465 (1992)).Sequentially, a clone in which valine is substituted for isoleucine-433was obtained. This plasmid vector expressing human SGLT2 in which thepeptide presented as sequence number 5 is fused to the carboxyl terminalalanine residue was designated KL29.

Sequence Number 1 ATGGAGGAGCACACAGAGGC Sequence Number 2GGCATAGAAGCCCCAGAGGA Sequence Number 3 AACCTCGAGATGGAGGAGCACACAGAGGCSequence Number 4 AACAAGCTTGGCATAGAAGCCCCAGAGGA Sequence Number 5KLGPEQKLISEEDLNSAVDHHHHHH

-   2) Preparation of the Cells Expressing Transiently Human SGLT2

KL29, the plasmid expressing human SGLT2, was transfected into COS-7cells (RIKEN CELL BANK RCB0539) by electroporation. Electroporation wasperformed with GENE PULSER II (Bio-Rad Laboratories) under thecondition: 0.290 kV, 975 μF, 2×10⁶ cells of COS-7 cell and 20 μg of KL29in 500 μL of OPTI-MEM I medium (Gibco-BRL: LIFE TECHNOLOGIES) in the 0.4cm type cuvette. After the gene transfer, the cells were harvested bycentrifugation and resuspended with OPTI-MEM I medium (1 mL/cuvette). Toeach well in 96-wells plate, 125 μL of this cell suspension was added.After overnight culture at 37° C. under 5% CO₂, 125 μL of DMEM mediumwhich is containing 10% of fetal bovine serum (Sanko Jyunyaku), 100units/mL sodium penicillin G (Gibco-BRL: LIFE TECHNOLOGIES), 100 μg/mLstreptomycin sulfate (Gibco-BRL: LIFE TECHNOLOGIES) was added to eachwell. These cells were cultured until the next day and then they wereused for the measurement of the inhibitory activity against the uptakeof methyl-α-D-glucopyranoside.

-   3) Measurement of the Inhibitory Activity Against the Uptake of    Methyl-α-D-glucopyranoside

After a test compounds was dissolved in dimethyl sulfoxide and dilutedwith the uptake buffer (a pH 7.4 buffer containing 140 mM sodiumchloride, 2 mM potassium chloride, 1 mM calcium chloride, 1 mM magnesiumchloride, 5 mM methyl-α-D-glucopyranoside, 10 mM2-[4-(2-hydroxyethyl)-1-piperazinyl]ethane sulfonic acid and 5 mMtris(hydroxymethyl)aminomethane), each diluent was used as test samplefor measurement of the inhibitory activity. After removal of the mediumof the COS-7 cells expressing transiently human SGLT2, to each well 200μL of the pretreatment buffer (a pH 7.4 buffer containing 140 mM cholinechloride, 2 mM potassium chloride, 1 mM calcium chloride, 1 mM magnesiumchloride, 10 mM 2-[4-(2-hydroxyethyl)-1-piperazinyl]ethane sulfonic acidand 5 mM tris(hydroxymethyl)aminomethane) was added, and the cells wereincubated at 37° C. for 10 minutes. After the pretreatment buffer wasremoved, 200 μL of the same buffer was added again, and the cells wereincubated at 37° C. for 10 minutes. The buffer for measurement wasprepared by adding of 7 μL of methyl-α-D-(U-14C)glucopyranoside(Amersham Pharmacia Biotech) to 525 μL of the prepared test sample. Forthe control, the buffer for measurement without test compound wasprepared. For estimate of the basal uptake in the absence of testcompound and sodium, the buffer for measurement of the basal uptake,which contains 140 mM choline chloride in place of sodium chloride, wasprepared similarly. After the pretreatment buffer was removed, 75 μL ofthe each buffer for measurement was added to each well, the cells wereincubated at 37° C. for 2 hours. After the buffer for measurement wasremoved, 200 μL of the washing buffer (a pH 7.4 buffer containing 140 mMcholine chloride, 2 mM potassium chloride, 1 mM calcium chloride, 1 mMmagnesium chloride, 10 mM methyl-α-D-glucopyranoside, 10 mM2-[4-(2-hydroxyethyl)-1-piperazinyl]ethane sulfonic acid and 5 mMtris(hydroxymethyl)aminomethane) was added to each well and immediatelyremoved. After two additional washing, the cells were solubilized byaddition of 75 μL of 0.2 N sodium hydroxide to each well. After the celllysates were transferred to the PicoPlate (Packard) and 150 μL ofMicroScint-40 (Packard) was added to each well, the radioactivity wasmeasured with microplate scintillation counter TopCount (Packard). Thedifference in uptake was obtained as 100% value by subtracting theradioactivity in the basal uptake from that in control and then theconcentrations at which 50% of uptake were inhibited (IC₅₀) werecalculated from the concentration-inhibition curve by least squaremethod. The results are shown in the following Table 1.

TABLE 1 Test compound IC₅₀ value (nM) Example 35 181 Example 36 441Example 37 346 Example 38 702 Example 39 185 Example 43 84 Example 44509 Example 45 441 Example 46 679 Example 48 415 Example 49 383 Example52 835 Example 55 280 Example 56 190 Example 58 634 WAY-123783 >100000

Test Example 2

Assay for the Facilitatory Effect on Urinary Glucose Excretion

Method A)

As experimental animal, overnight fasted SD rats (SLC, male, 5 weeks ofage, 120–150 g) were used. Test compound (25.40 mg) was suspended in 762μL of ethanol and dissolved by adding of 3.048 mL of polyethylene glycol400 and 3.81 mL of saline and then 3.3 mg/mL solution was prepared. Apart of this solution was diluted with the solvent (saline:polyethyleneglycol 400:ethanol=5:4:1) and then each solution at the concentration of3.3, 1 or 0.33 (mg/mL) was prepared. Each of these solutions wassubcutaneously administrated to the rats at the dose of 3 mL/kg (10, 3and 1 mg/kg). For the control, just only the solvent(saline:polyethylene glycol 400:ethanol=5:4:1) was subcutaneouslyadministrated at the dose of 3 mL/kg. Immediately after thissubcutaneous administration, 200 g/L glucose solution was orallyadministered at the dose of 10 mL/kg (2 g/kg). The subcutaneousadministration was performed with 26G needle and 1 mL syringe. The oraladministration was performed with gastric tube for rat and 2.5 mLsyringe. The head count in one group was 3. Collection of urine wasperformed in metabolic cage after these administrations were finished.The sampling time for collection of urine was 4 hours after the glucoseadministration. After collection of urine was finished, the urine volumewas recorded and the urinary glucose concentration was measured. Theglucose concentration was measured with a kit for laboratory test:Glucose B-Test WAKO (Wako Pure Chemical Industries, Ltd.). The amount ofurinary glucose excretion in 4 hours per 1 body was calculated fromurine volume and urinary glucose concentration.

Method B)

As experimental animal, overnight fasted SD rats (SLC, male, 7 weeks ofage, 180–220 g) were used. A test compound (10 mg) was suspended ordissolved in 300 μL of ethanol and dissolved by adding of 1.2 mL ofpolyethylene glycol 400 and 1.5 mL of saline and then 3.3 mg/mL solutionwas prepared. A part of this solution was diluted with the solvent(saline:polyethylene glycol 400:ethanol=5:4:1) and then each solution atthe concentration of 3.3, 0.33 or 0.033 (mg/mL) was prepared. After thebody weights of the rats were measured, the test compound solution wasadministrated by intravenous injection to the tail vein at the dose of 3mL/kg (10, 1 and 0.1 mg/kg). For the control, just only the solvent(saline:polyethylene glycol 400:ethanol=5:4:1) was administrated byintravenous injection to the tail vein at the dose of 3 mL/kg.Immediately after this intravenous administration, 200 g/L glucosesolution was orally administered at the dose of 10 mL/kg (2 g/kg). Theintravenous administration was performed with 26 G needle and 1 mLsyringe. The oral administration was performed with gastric tube for ratand 2.5 mL syringe. The head count in one group was 3. Collection ofurine was performed in metabolic cage after the glucose administrationwas finished. The sampling time for collection of urine was 24 hoursafter the glucose administration. After collection of urine wasfinished, the urine volume was recorded and the urinary glucoseconcentration was measured. The glucose concentration was measured witha kit for laboratory test: Glucose B-Test WAKO (Wako Pure ChemicalIndustries, Ltd.). The amount of urinary glucose excretion in 24 hoursper 200 g of body weight was calculated from urine volume, urinaryglucose concentration and body weight.

The results are shown in the following Table 2.

TABLE 2 Test Dose Amount of Urinary compound Method (mg/kg) GlucoseExcretion (mg) Example 35 B 0.1 16 1 74 10 188 Example 45 A 1 22.1 383.2 10 153.3 B 0.1 2 1 45 10 132

Test Example 3

Acute Toxicity Test

Method A)

By adding of 0.5% sodium carboxymethylcellulose solution to the testcompound, 100 mg/mL suspension was prepared. As experimental animal,male 6–7 weeks of age ICR mice fasted for 4 hours (Clea Japan, 28–33 g,5 animals in each group) were used. The test suspension described abovewas orally administrated to the experimental animals described above atthe dose of 10 mL/kg (1000 mg/kg) and then observation was performeduntil 24 hours after the administration.

Method B)

By adding of the solvent (saline:polyethylene glycol 400:ethanol=5:4:1)to the test compound, 200 mg/mL suspension was prepared. As experimentalanimal, male 5 weeks of age ICR mice fasted for 4 hours (Clea Japan,26–33 g, 5 animals in each group) were used. The test suspensiondescribed above was subcutaneously administrated to the experimentalanimals described above at the dose of 3 mL/kg (600 mg/kg) and thenobservation was performed until 24 hours after the administration.

The results are shown in the following Table 3.

TABLE 3 Test compound Method Death number Example 35 B 0/5 Example 45 A0/5

INDUSTRIAL APPLICABILITY

The glucopyranosyloxybenzylbenzene derivatives represented by the abovegeneral formula (I) of the present invention and pharmaceuticallyacceptable salts thereof have an inhibitory activity in human SGLT2 andexert an excellent hypoglycemic effect by excreting excess glucose inthe urine through preventing the reabsorption of glucose at the kidney.Therefore, agents for the prevention or treatment of diabetes, diabeticcomplications, obesity or the like can be provided by comprising theglucopyranosyloxybenzylbenzene derivative represented by the abovegeneral formula (I) of the present invention or pharmaceuticallyacceptable salt thereof.

In addition, the compounds represented by the above general formulae (V)and (VII), and salts thereof are important as intermediates in theproduction of the compounds represented by the above general formula (I)and pharmaceutically acceptable salts thereof. Accordingly, thecompounds represented by the above general formula (I) of the presentinvention and pharmaceutically acceptable salts thereof can be readilyprepared via these compounds.

1. A benzylpyrazole derivative represented by the general formula:

wherein R^(2′) represents a lower alkyl group, a halo(lower alkyl) groupor a halogen atom; and R^(3′) represents a lower alkyl group; or a saltthereof.